To investigate the molecular events that regulate visual adaptation, mouse genetics will be used to target specific components of phototransduction. Electrophysiological measurements of the photoreceptors from these genetically-engineered mice will be used to study the role of particular components under in vivo conditions and under real-time kinetics. Biochemical assays will be used in conjunction with these measurements to delineate the molecular mechanisms behind the physiologic phenotypes. Using this multi-disciplinary approach, the investigator proposes: (1) to systematically remove the known Ca2+-feedback loops by targeted disruption of Ca2+ binding proteins that are thought to mediate the feedback; and (2) to eliminate regulation by Ca2+-calmodulin on the cyclic GMP (cGMP)-gated channel, using mice harboring a target mutation on the beta-subunit of the cGMP-gated channel that disrupts the overall adaptation process, and assess the role of Ca2+-feedback in regulating visual adaptation. Further studies will investigate the recovery mechanisms involving guanylate cyclases (GCs) and guanylate cyclase activating proteins (GCAPs) in rod photoreceptor response. Finally, the relationship between elevated cGMP and photoreceptor cell-death will be investigated.